ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9820T>G (p.Leu3274Val) (rs80359244)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222518 SCV000278335 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000112814 SCV000145716 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
GeneDx RCV000276881 SCV000329149 uncertain significance not provided 2016-08-09 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9820T>G at the cDNA level, p.Leu3274Val (L3274V) at the protein level, and results in the change of a Leucine to a Valine (TTG>GTG). This variant, also known as BRCA2 10048T>G using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu3274Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Leu3274Val occurs a position that is conserved across species and is not located in a known functional domain (Cole 2011). Protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. However, multiple splicing models predict that this variant may create a cryptic splice donor site and lead to abnormal splicing; though, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 Leu3274Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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